Remedies for sepsis

ABSTRACT

A therapeutic agent for sepsis and various symptoms accompanying sepsis (such as septic shock, disseminated intravascular coagulation syndrome, adult respiratory distress syndrome and multiple organ dysfunction) is disclosed. The therapeutic agent for sepsis according to the present invention comprises as an effective ingredient an opioid κ receptor agonist compound such as (−)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β[N-methyl-trans-3-(3-furyl)acrylamide] oxide derivative. The opioid κ receptor agonist compound may be administered as it is or in the form of a pharmaceutical composition prepared by mixing the compound with a known pharmaceutically acceptable acid, carrier or vehicle orally or parenterally.

TECHNICAL FIELD

[0001] The present invention relates to a novel therapeutic agent forsepsis containing an opioid κ receptor agonist.

BACKGROUND ART

[0002] Sepsis is a severe systemic infectious disease in which bacteriacontinuously or intermittently enter the blood from an infection focus,which is caused by diseases such as infectious diseases, cirrhosis,renal failure, diabetes and dystocia, or by therapies against injury ordisease, such as indwelling catheter, transfusion device, dialysis ortracheostomy. In its broader sense, sepsis is not restricted to theinvasion by a microorganism into a host, but is defined to includeclinical conditions of infectious diseases, in which two or more of thefollowing are met: (1) body temperature >38° C. or <36° C.; (2) heartrate >90 beats/min.; (3) frequency of respiration >20 breaths/min. orPaCO₂<32 mmHg; (4) number of leukocytes >12,000/μl or <4000/μl, or ratioof stab neutrophil>10%. Recently, the pathological conditions exhibitingthese symptoms are called systemic inflammatory response syndrome (SIRS)(Crit. Care Med., 20:864-874, 1992). Sepsis further includes organdysfunction, severe sepsis complicated with hypoperfusion orhypotension, lactic acidosis, hypouresis and septic shock complicatedwith consciousness disorder (Chest,101:1644-1655,1992). Severe sepsisand septic shock induce disseminated intravascular coagulation syndrome(DIC), adult respiratory distress syndrome (ARDS) and multiple organdysfunction (MODS).

[0003] The causative bacteria of sepsis are mainly staphylococci,streptococci, Escherichia coli, Pseudomonas aeruginosa, Klebsiella andEnterobacter. By the infection of these bacteria, high fever, chill,tachycardia and strong systemic symptoms are exhibited, and existence ofthe infective bacteria is often confirmed in the arterial blood, venousblood, spinal fluid and bone marrow fluid.

[0004] Recently, due to the development of various strong antibiotics,sepsis caused by these bacteria is decreasing. However, sepsis caused bynew bacteria such as MRSA, which acquired a resistant gene isincreasing. Reflecting the increase of treatments using indwellingcatheter or transfusion device, dialysis, and invasive treatments andsurgery such as tracheostomy, there is a tendency that the larger thescale of the hospital, the more the occurrence of sepsis. Further,frequency of sepsis is increasing among those having poor resistance toinfections, such as newborns, elder people, patients suffering fromhematopoietic organ tumors and patients whose immunities are decreaseddue to administration of adenocorticotropic hormones or anticanceragents. Thus, sepsis is continuously increasing in spite of thedevelopment of medicine.

[0005] A method for prevention or therapy of sepsis now employed iscarried out by administering the best antibiotic against the causativebacterium after detecting the causative bacterium and determining thesensitivities thereof to antibiotics, and by simultaneously promotingthe defending ability of the host by fluid replacement, replenishment ofelectrolytes, improvement of hypoproteinemia, replenishment ofnutrients, administration of γ-globulin and the like (Masataka KATSU,Encyclopedia of medical sciences,37:263-265,1984). In cases where theshock unfortunately appears, treatments such as removal of lesion bysurgery, improvement of circulatory dysfunction, administration ofopsonin-activating substances, administration of adenocorticotropichormones, administration of synthetic protease inhibitors, and the likeare carried out. However, since the symptoms of the underlying basaldisease and the symptoms of sepsis overlap, clear diagnosis is noteasily carried out, which often gives difficulty in the prevention andtherapy of sepsis. In cases where the septic shock occurs, theprevention and therapy are difficult. Thus, sepsis is a disease whichgives a high death rate even at present.

[0006] The death rate of sepsis varies from 10%-20% s to 50% dependingon the report. Forty percent of sepsis cases are complicated with septicshock, and the prognosis of the shock is bad. There is a report whichshows the death rate of the shock is 77 to 90% (New Development ofSepsis, pp3-8, Medicine Journal Co., Ltd., 1998, Ann Intern Med 115:457-469, 1991). Therefore, the primary object of the therapy is theprevention of the septic shock. If the changes which occurs in theinitial stage of the shock are grasped and early diagnosis is attained,early treatment can be attained and improvement of prognosis isexpected. However, although a number of anti-shock drugs and therapeuticmethods have been studied, almost none of them were judged effective.

[0007] It is thought that sepsis is caused by inflammatory cytokinessuch as tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6(IL-6) and interleukin 8 (IL-8), which are excessively produced bymonocytes, macrophages, vascular endothelial cells and the like inresponse to the infectious stimuli (such as bacterial cells per se,endotoxins, cell wall components which are peptide glycan/teichoic acidcomplexes and exotoxins). By the excessively produced inflammatorycytokines, eicosanoid and lipid mediators of platelet-activating factorare released, and the cytokine net work is activated by the interactionthereof, so that the inflammatory reaction is amplified. During thisprocess, complement system, coagulation system, kinin system andadrenocorticotropic hormone/endorphin system are also activated, and thesystemic inflammatory reaction of which underlying symptom is vascularendothelial disorder is induced. For expression of circulatory disordersor histotoxic disorders, participation of elastase originated fromgranulocytes and active oxygen has been shown (New Development ofSepsis, pp3-8, Medicine Journal Co., Ltd., 1998).

[0008] Therefore, a number of clinical tests of the therapeutic methodswhich inhibit the inflammatory cytokines, represented by administrationof substances that inhibit the inflammatory cytokines have been carriedout. However, all of them were unsuccessful (Lancet,351:929-933,1998,JAMA,271:1836-1843,1994). Bone suggested that the reason for the failureof the tests may be the homeostasis in the body by which an action inthe body necessarily accompanies a counteraction therefor so that theyare balanced (Crit. Care Med., 24:1125-1128,1996). In fact, it is knownthat surgery or severe acute pancreatitis induces both the inflammatorycytokines and the anti-inflammatory cytokines or inflammatorycytokine-inhibiting substances (Intensive Care, 10;815-822,1998). If theinduction of the anti-inflammatory cytokines is too strong, anergy ispresented or the patient becomes easily infective. Thisanti-inflammatory cytokines-dominant state is called compensatoryanti-inflammatory response syndrome (CARS), and participates in theonset of organ dysfunction in sepsis together with SIRS. That is, thepathological state of sepsis is double-faced, and it is important forthe therapy to control both the inflammatory cytokine reactions and theanti-inflammatory cytokine reactions. Therefore, it is thought thattherapeutic effects of the therapies in which only one of the reactionsis inhibited by inhibition of inflammatory cytokines or the like werenot exhibited.

[0009] Although intensive care developed during this 20 years, the deathrate of sepsis is kept high and there are substantially no effectiveremedies. The reason therefor is that the pathological conditions ofsepsis have not yet been completely understood (Nath. J.Med.,55:132-141,1999). It is also a reason therefor that therapeuticeffects of drugs were studied by administering the test drugs beforeinducing the experimental sepsis in non-clinical animal tests.

[0010] Opioid drugs represented by morphine are widely used clinicallyas analgesics. It is thought that an opioid binds to an opioid receptorexisting on the cell membrane and changes ion channels or enzymesthrough G protein, thereby exhibiting its pharmacological effectsThereare three types of opioid receptors called δ, κ and μ, and structures ofthese receptors were clarified by the cloning of the genes (Pharmacol.Rev.,48:567-592,1996). Most of the opioids clinically used are the drugswhich act on t receptor. Known agonists include morphine, codeine,oxycodone, pethidine and fentanyl, and known antagonists includenaloxone and levallorphan. Other clinically used opioids includebutorphanol, pentazocine and eptazocine, and they act on both [receptorand κ receptors (Basis and Clinic of Opioids, pp9-15, MIX Co., Ltd.,2000). Known pharmacological actions of the compounds which act on μreceptor include actions causing analgesia, miosis, respiratorydepression, emesis or nausea, constipation, euphoria and pruritus.

[0011] As for the compounds which selectively act on K receptor, nodrugs which can be clinically used have been obtained. However, a numberof compounds which can be non-clinically used are known, and clinicaltests of some of them are now being conducted (Exp. Opin. Invest.Drugs,6:1351-1368,1997). Known pharmacological actions of the compoundswhich act on κ receptor include actions causing analgesia, sedation,discomfort, diuresis, cell protection and antipruritus.

[0012] As for the actions of opioids on sepsis, the action of morphinewhich is a μ agonist, and the action of naloxone which is a μantagonist, are reported. The former is reported to decrease survivalrate of experimental sepsis models, and the latter, naloxone, isreported to suppresses fever of experimental sepsis models (J.Neuroimmuneol.,95:107-114,1999, Eur. J. Pharmacol.,401:161-165,2000).U.S. Pat. Nos. 4,267,182 (1981) and 4,434,168 (1984) describe narcoticantagonists for therapies of various shocks. However, compounds whichselectively act on K receptor are not described. It is not clear how acompound which acts on K receptor behaves with respect to sepsis.

[0013] On the other hand, U.S. Pat. No. 5,482,930 (1996) disclosesanti-inflammation actions of des-Tyr dynorphine which is one of thecompounds that act on κ receptor and of analogues thereof.

DISCLOSURE OF THE INVENTION

[0014] An object of the present invention is to provide a therapeuticagent for sepsis and various symptoms accompanying sepsis (such asseptic shock, disseminated intravascular coagulation syndrome, adultrespiratory distress syndrome and multiple organ dysfunction).

[0015] As a result of intensive study by the present inventors forovercoming the above-described problem, the present inventors discoveredthat opioid κ agonist compounds serve as therapeutic agents for sepsisand various symptoms accompanying sepsis, thereby completing the presentinvention.

[0016] That is, the present invention provides a therapeutic agent forsepsis comprising an opioid κ receptor agonist compound as an effectiveingredient. The term “opioid κ receptor agonist compound” means acompound which has selectivity to κ receptor irrespective of thechemical structural specificity. Particularly, the compounds describedin Japanese Patent No. 2525552, WO98/23290, U.S. Pat. No. 4,145,435(1979), U.S. Pat. No. 4,360,531 (1982), U.S. Pat. No. 4,359,476 (1982),EP Patent No. 108602 (1983), U.S. Pat. No. 4,855,316 (1989), EuropeanPatent No. 372466 (1989), European Patent No. 393696 (1990), U.S. Pat.No. 4,906,655 (1990), U.S. Pat. No. 4,438,130 (1984), U.S. Pat. No.4,663,343 (1987), U.S. Pat. No. 5,760,023 (1998), Japanese Laid-open PCTApplication No. 11-512075 (1999) and so on. More particularly, thepresent invention provides:

[0017] a therapeutic agent for sepsis comprising, as an effectiveingredient, an opioid K receptor agonist compound which is a morphinanderivative represented by the following Formula (I):

[0018] [wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₆-C₁₂ aryl, C₇-C₁₃aralkyl, C₄-C₇ alkenyl, allyl, C₁-C₅ furan-2-ylalkyl or C₁-C₅thiophene-2-ylakyl; R₂ represents hydrogen, hydroxy, nitro, C₁-C₅alkanoyloxy, C₁-C₅ alkoxy, C₁-C₅ alkyl or —NR⁹R¹⁰ wherein R⁹ representshydrogen or C₁-C₅ alkyl and R¹⁰ represents hydrogen or C₁-C₅ alkyl or—C(═O)R¹¹ wherein R¹¹ represents hydrogen, phenyl or C₁-C₅ alkyl; R³represents hydrogen, hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; Arepresents —XC(═Y)—, —XC(═Y)Z-, —X— or —XSO₂— (wherein X, Y and Zindependently represent NR⁴,S or O wherein R⁴ represents hydrogen, C₁-C₅linear or branched alkyl or C₆-C₁₂ aryl, R⁴s in the formula may be thesame or different); B represents valence bond, C₁-C₁₄ linear or branchedalkylene (with the proviso that said alkylene may have at least onesubstituent selected from the group consisting of C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro,cyano, trifluoromethyl and phenoxy, and that 1 to 3 methylene groups insaid alkylene may be substituted with carbonyl group(s)), C₂-C₁₄ linearor branched acyclic unsaturated hydrocarbon containing 1 to 3 doublebonds and/or triple bonds (with the proviso that said acyclicunsaturated hydrocarbon may have at least one substituent selected fromthe group consisting of C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy,fluorine, chlorine, bromine, iodine, amino, nitro, cyano,trifluoromethyl and phenoxy, and that 1 to 3 methylene groups in saidacyclic unsaturated hydrocarbon may be substituted with carbonylgroup(s)), or C₁-C₁₄ linear or branched saturated or unsaturatedhydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or aminobonds (with the proviso that a hetero atom does not directly binds to A,and that 1 to 3 methylene groups in said acyclic unsaturated hydrocarbonmay be substituted with carbonyl group(s)); R⁵ represents hydrogen or anorganic group having a skeleton selected from those shown below

[0019] (wherein Q represents NH, O or S; T represents CH₂, NH, S or O; lrepresents an integer of 0 to 5; and m and n independently representintegers of not less than 0, the total of m and n being not more than 5;each of said organic groups may have at least one substituent selectedfrom the group consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro,cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy andmethylenedioxy); R⁶ represents hydrogen; R⁷ represents hydrogen,hydroxy, C₁-C₅ alkoxy or C₁-C₅ alkanoyloxy; or R⁶ and R⁷ cooperativelyrepresent —O—, —CH₂— or —S—; and R⁸ represents hydrogen, C₁-C₅ alkyl orC₁-C₅ alkanoyl]

[0020] or a pharmaceutically acceptable acid addition salt thereof;

[0021] a therapeutic agent for sepsis comprising, as an effectiveingredient, an opioid κ receptor agonist compound which is a morphinanquaternary ammonium salt derivative represented by the following Formula(II):

[0022] [wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₇-C₁₃ aralkyl, C₄-C₇alkenyl or allyl; R² represents hydrogen, hydroxy, nitro, C₁-C₅alkanoyloxy, C₁-C₅ alkoxy or C₁-C₅ alkyl; R³ represents hydrogen,hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; R⁴ represents hydrogen,C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl; A represents C₁-C₆alkylene, —CH═CH— or —C≡C—; R⁵ represents hydrogen or an organic grouphaving a skeleton selected from those shown below

[0023] (wherein Q represents O or S; T represents CH₂, NH, S or O; lrepresents an integer of 0 to 5; and m and n independently representintegers of not less than 0, the total of m and n being not more than 5;each of said organic groups may have at least one substituent selectedfrom the group consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano,isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy);

[0024] R₆ represents C₁-C₅ alkyl or allyl; and X represents apharmaceutically acceptable counter ion];

[0025] a therapeutic agent for sepsis comprising, as an effectiveingredient, an opioid K receptor agonist compound which is aoxide-N-oxide derivative represented by the following Formula (III):

[0026] [wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₆-C₁₂ aryl, C₇-C₁₃aralkyl, C₄-C₇ alkenyl or allyl; R² represents hydrogen, hydroxy, nitro,C₁-C₅ alkanoyloxy, C₁-C₅ alkoxy or C₁-C₅ alkyl; R³ represents hydrogen,hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; R⁴ represents hydrogen,C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl; A represents C₁-C₆alkylene, —CH═CH— or —C≡C—; R⁵ represents hydrogen or an organic grouphaving a skeleton selected from those shown below

[0027] (wherein T represents CH₂ or O; l represents an integer of 0 to5; and m and n independently represent integers of not less than 0, thetotal of m and n being not more than 5; each of said organic groups mayhave at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy)]

[0028] or a pharmaceutically acceptable acid addition salt thereof;

[0029] a therapeutic agent for sepsis comprising, as an effectiveingredient, an opioid κ receptor agonist compound which is a compoundrepresented by the following Formula (IV):

[0030] [wherein the wavy lines (˜) between the cyclohexane ring and thetwo nitrogen atoms represent bonds which are cis or trans with respectto the cyclohexane ring; A represents valence bond, —(CH₂)_(q)—,—CH(CH₃)— or —X(CH₂)_(n)— (wherein q represents an integer of 1 to 4; nrepresents an integer of 1 to 4; and X represents O or S); Ar representsa carbocyclic aromatic ring, heterocyclic aromatic ring, bicarbocyclicaromatic ring, tricarbocyclic aromatic ring or diphenylmethyl, each ofsaid carbocyclic aromatic ring, heterocyclic aromatic ring,bicarbocyclic aromatic ring, tricarbocyclic aromatic ring anddiphenylmethyl may have one or more substituents selected from the groupconsisting of hydrogen, halogen, trifluoromethyl, nitro, C₁-C₃ alkoxy,hydroxy, azide, C₁-C₃ alkyl, methanesulfonyl, cyano, amino, C₁-C₃alkoxycarbonyl, C₁-C₃ alkanoyloxy and C₁-C₃ acylamino represented by—NHC(═O)R₇ (wherein R₇ represents hydrogen or C₁-C₂ alkyl); R representshydrogen, C₁-C₃ alkyl or allyl; R¹ and R² independently representhydrogen, C₁-C₃ alkyl or allyl, or R¹, R² and the nitrogen atom to whichthey bind cooperatively represent azetidinyl, pyrrolidinyl,3-hydroxypyrrolidinyl, 3-fluoropyrrolidinyl, morpholinyl, piperidinyl or3,4-dehydropiperidinyl; R³, R⁴, R₅ and R₆ independently representhydrogen, hydroxy, OR⁸ or OC(═O)R₉, or R⁵ and R⁶ cooperatively represent-E-CH₂—CH₂-E-, =E, —CH₂—CH₂—CH₂-Z- or —CH₂—CH₂-Z-CH₂— (wherein Zrepresents oxygen (—O—), —NR¹⁰—, sulfur (—S—), —S(═O)— or —S(═O)₂—; Erepresents N—OH, N—OC(═O)CH₃, oxygen or sulfur; R⁸ represents C₁-C₃alkyl; and R⁹ represents hydrogen or C₁-C₃ alkyl]

[0031] or a pharmaceutically acceptable acid addition salt thereof; and

[0032] a therapeutic agent for sepsis comprising, as an effectiveingredient, an opioid K receptor agonist compound which is a compoundrepresented by the following Formula (V):

(D)Phe-R1-R2-R3-Q  (V)

[0033] [wherein R1 represents (D)NapAla or (D)Phe; R2 represents (D)Nle,Trp or (D)Ile; R3 represents (D)Arg or (D)ChAla; Q is a C-terminalstructure of the peptide and represents —(C═O)OH or —(C═O)NXY (wherein Xrepresents hydrogen or C₁-C₆ alkyl; and Y represents hydrogen or C₁-C₆alkyl)]

[0034] or a pharmaceutically acceptable acid addition salt thereof.

[0035] In the present specification, the term “organic group having askeleton” in Formulae (I), (II), (III) and so on means the monovalentgroup formed by elimination of one hydrogen atom from the ringconstituting each of the compounds shown as skeletons, and themonovalent group just mentioned above having at least one substituentdescribed above. In the present specification, the followingabbreviations are used for designating amino acid residues: TABLE 1Amino Acid Abbreviation alanine Ala arginine Arg cyclohexylalanine ChAlaisoleucine Ile naphthylalanine NapAla norleucine Nle phenylalanine Phetryptophan Trp

[0036] Amino acids are designated as described above by the well-knowncodes. “(D)” indicates amino acids having D-configuration in contrast tothe naturally occurring L-amino acids. The amino acids of whichconfigurations are not indicated are (L)-amino acids.

[0037] The present invention also provides use of the opioid κ receptoragonist compound for the production of a therapeutic agent for sepsis.The present invention further provides a therapeutic method for sepsiscomprising administering the opioid K receptor agonist compound to apatient suffering from sepsis.

BRIEF DESCRIPTION OF THE DRAWING

[0038]FIG. 1 is a drawing which shows that Compound 1 increases thesurvival rate of sepsis model animals.

BEST MODE FOR CARRYING OUT THE INVENTION

[0039] As mentioned above, the present invention provides a therapeuticagent for sepsis comprising an opioid κ receptor agonist compound as aneffective ingredient. The term “opioid κ receptor agonist compound”means a compound which has selectivity to κ receptor irrespective of thechemical structural specificity. Particularly, the compounds describedin Japanese Patent No. 2525552, WO98/23290, U.S. Pat. No. 4,145,435(1979), U.S. Pat. No. 4,360,531 (1982), U.S. Pat. No. 4,359,476 (1982),EP Patent No. 108602 (1983), U.S. Pat. No. 4,855,316 (1989), EuropeanPatent No. 372466 (1989), European Patent No. 393696 (1990), U.S. Pat.No. 4,906,655 (1990), U.S. Pat. No. 4,438,130 (1984), U.S. Pat. No.4,663,343 (1987), U.S. Pat. No. 5,760,023 (1998), Japanese Laid-open PCTApplication No. 11-512075 (1999) and so on. More particularly, thepresent invention provides: a therapeutic agent for sepsis comprising,as an effective ingredient, an opioid κ receptor agonist compound whichis a morphinan derivative represented by the following Formula (I):

[0040] [wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₆-C₁₂ aryl, C₇-C₁₃aralkyl, C₄-C₇ alkenyl, allyl, C₁-C₅ furan-2-ylalkyl or C₁-C₅thiophene-2-ylakyl; R² represents hydrogen, hydroxy, nitro, C₁-C₅alkanoyloxy, C₁-C₅ alkoxy, C₁-C₅ alkyl or —NR⁹R¹⁰ wherein R⁹ representshydrogen or C₁-C₅ alkyl and R¹⁰ represents hydrogen or C₁-C₅ alkyl or—C(═O)R¹¹ wherein R¹¹ represents hydrogen, phenyl or C₁-C₅ alkyl; R³represents hydrogen, hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; Arepresents —XC(═Y)—, —XC(═Y)Z-, —X— or —XSO₂— (wherein X, Y and Zindependently represent NR⁴, S or O wherein R⁴ represents hydrogen,C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl, R⁴s in the formula may bethe same or different); B represents valence bond, C₁-C₁₄ linear orbranched alkylene (with the proviso that said alkylene may have at leastone substituent selected from the group consisting of C₁-C₅ alkoxy,C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino,nitro, cyano, trifluoromethyl and phenoxy, and that 1 to 3 methylenegroups in said alkylene may be substituted with carbonyl group(s)),C₂-C₁₄ linear or branched acyclic unsaturated hydrocarbon containing 1to 3 double bonds and/or triple bonds (with the proviso that saidacyclic unsaturated hydrocarbon may have at least one substituentselected from the group consisting of C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy,hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano,trifluoromethyl and phenoxy, and that 1 to 3 methylene groups in saidacyclic unsaturated hydrocarbon may be substituted with carbonylgroup(s)), or C₁-C₁₄ linear or branched saturated or unsaturatedhydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or aminobonds (with the proviso that a hetero atom does not directly binds to A,and that 1 to 3 methylene groups in said acyclic unsaturated hydrocarbonmay be substituted with carbonyl group(s)); R⁵ represents hydrogen or anorganic group having a skeleton selected from those shown below

[0041] (wherein Q represents NH, O or S; T represents CH₂, NH, S or O; lrepresents an integer of 0 to 5; and m and n independently representintegers of not less than 0, the total of m and n being not more than 5;each of said organic groups may have at least one substituent selectedfrom the group consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro,cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy andmethylenedioxy); R⁶ represents hydrogen; R⁷ represents hydrogen,hydroxy, C₁-C₅ alkoxy or C₁-C₅ alkanoyloxy; or R⁶ and R⁷ cooperativelyrepresent —O—, —CH₂— or —S—; and R⁸ represents hydrogen, C₁-C₅ alkyl orC₁-C₅ alkanoyl]

[0042] or a pharmaceutically acceptable acid addition salt thereof.

[0043] In Formula (I), as R¹, C₁-C₅ alkyl, C₄-C₇ cycloalkylmethyl, C₅-C₇cycloalkenylmethyl, C₇-C₁₃ phenylalkyl, C₄-C₇ alkenyl, allyl, C₁-C₅furan-2-yl-alkyl and C₁-C₅ thiophene-2-yl-alkyl are preferred, andmethyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl,benzyl, phenethyl, furan-2-yl-methyl and thiophene-2-yl-methyl areespecially preferred.

[0044] As R², hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl,propyl, amino, dimethylamino, acetylamino and benzoylamino arepreferred. Among these, hydrogen, hydroxy, nitro, acetoxy, methoxy anddimethylamino are preferred, and hydrogen, hydroxy, acetoxy and methoxyare particularly preferred.

[0045] As R³, hydrogen, hydroxy, acetoxy and methoxy preferred, andhydroxy, acetoxy and methoxy are especially preferred.

[0046] Examples of the groups represented by A include —NR⁴C(═O)—,—NR₄C(═S)—, —NR⁴C(═O)O—, —NR₄C(═O)NR⁴—, —NR⁴C(═S)NR⁴-, —NR₄C(═O)S—,—OC(═O)—OC(═O)O—, —SC(═O)—, —NR⁴—, —, —NR⁴SO₂—, —OSO₂— and the like. AsA, —XC(═Y)—(wherein X represents NR⁴, S or O; Y represents O wherein R⁴represents hydrogen or C₁-C₅ alkyl), —XC(═Y)Z-, —X— and —XSO₂— (whereinX represents NR⁴, Y represents O or S, Z represents NR⁴ or O wherein R⁴represents hydrogen or C₁-C₅ alkyl) are preferred. Among these, —NRC(═O)—, —NR⁴C(═S)—, —NR⁴C(═O)O—, —NR⁴C(═O)NR⁴—, —NR⁴C(═S)NR⁴— and—NR⁴SO₂— are particularly preferred, —NR⁴C(═O)—, —NR⁴C(═O)NR⁴— and—NR⁴C(═O)O— are more preferred, and —NR⁴C(═O)— and —NR⁴C(═O)NR⁴— areespecially preferred.

[0047] As R⁴, hydrogen and C₁-C₅ linear or branched alkyl are preferred.Especially, C₁-C₅ linear or branched alkyl are preferred, and amongthese, methyl, ethyl, propyl, butyl and isobutyl are preferred.

[0048] As B, —(CH₂)_(n)-(n=O-10), —(CH₂)_(n)—C(═O)-(n=1-4),—CH═CH—(CH₂)_(n)-(n=0-4), —C≡C—(CH₂)_(n)-(n=0-4), —CH₂—O—, —CH₂—S—,—CH₂—NH—, —(CH₂)₂—O—CH₂— and —CH═CH—CH═CH—(CH₂)_(n)—(n=0-4) arepreferred, and (CH₂)_(n)-(n=1-3), —CH═CH—(CH₂)_(n)-(n=0-4),—C≡C—(CH₂)_(n)-(n=0-4), —CH₂—O—, —CH₂—S— and —CH₂—NH— are especiallypreferred. Among these, C₁-C₃ linear alkylene, —CH═CH—, —C≡C—, —CH₂O—,—CH₂S— and —CH₂—NH— are preferred, and —CH═CH— and —C≡C— are especiallypreferred (needless to say, these preferred examples include thosehaving the above-described substituents).

[0049] As R⁵, hydrogen and organic groups having skeletons shown below

[0050] (wherein Q represents O or S; each of said organic groups mayhave at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy) are preferred.Among these, hydrogen, phenyl, thienyl, and furanyl (each of saidorganic groups may have at least one substituent selected from the groupconsisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy,fluorine, chlorine, bromine, iodine, amino, nitro, cyano,isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy)are preferred.

[0051] More specific preferred examples include hydrogen, phenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 3,4-dihydroxyphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 3,4-difluorophenyl, perfluorophenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl,2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl,4-nitrophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,3,4-methylenedioxyphenyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,cyclopentyl and cyclohexyl, but examples of R⁵ are not restrictedthereto.

[0052] R⁶ and R⁷ preferably form —O—, —CH₂— or —S— cooperatively, andespecially preferably form —O— cooperatively.

[0053] As R⁸, hydrogen, C₁-C₅ alkyl and C₁-C₅ alkanoyl are preferred.Among these, hydrogen, methyl, ethyl and propyl are preferred, andhydrogen is especially preferred.

[0054] Among the compounds represented by Formula (I), preferred arethose wherein R¹ is methyl, ethyl, propyl, butyl, isobutyl,cyclopropylmethyl, allyl, benzyl or phenethyl; R² and R³ independentlyare hydrogen, hydroxy, acetoxy or methoxy; A is —XC(═Y)— (wherein Xrepresents NR⁴, S or O; Y represents O wherein R⁴ represents hydrogen orC₁-C₅ alkyl), —NR⁴C(═Y)Z- (wherein Y represents O or S; Z represents NR⁴or O wherein R⁴ represents hydrogen or C₁-C₅ alkyl), —NR⁴— (wherein R⁴represents hydrogen or C₁-C₅ alkyl) or —NR⁴XSO₂— (wherein R⁴ representshydrogen or C₁-C₅ alkyl); B is C₁-C₃ linear alkylene, —CH═CH—, —C≡C—,—CH₂—O—, —CH₂—S— or —CH₂—NH—; R⁵ is hydrogen or an organic group havinga skeleton selected from those shown below

[0055] (wherein Q represents O or S; each of said organic groups mayhave at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy); R⁶ and Rcooperatively form —O—; and R⁸ is hydrogen; and more preferred are thosewherein R¹ is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl,allyl, benzyl or phenethyl; R² and R³ independently are hydrogen,hydroxy, acetoxy or methoxy; A is —NR⁴C(═O)— or —NR⁴C(═O)O— (wherein Rrepresents C₁-C₅ alkyl); B is C₁-C₃ linear alkylene, —CH═CH—, —C≡C—,—CH₂—O—, —CH₂—S— or —CH₂—NH—; R⁵ is hydrogen or an organic group havinga skeleton selected from those shown below

[0056] (wherein Q represents O or S; each of said organic groups mayhave at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy); R⁶ and R⁷cooperatively form —O—; and R⁸ is hydrogen.

[0057] The compounds represented by Formula (I) may be produced by themethod described in Japanese Patent No. 2525552.

[0058] The present invention also provides, particularly, a therapeuticagent for sepsis comprising, as an effective ingredient, an opioid κreceptor agonist compound which is a morphinan quaternary ammonium saltderivative represented by the following Formula (II):

[0059] [wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₇-C₁₃ aralkyl, C₄-C₇alkenyl or allyl; R² represents hydrogen, hydroxy, nitro, C₁-C₅alkanoyloxy, C₁-C₅ alkoxy or C₁-C₅ alkyl; R³ represents hydrogen,hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; R⁴ represents hydrogen,C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl; A represents C₁-C₆alkylene, —CH═CH— or —C≡C—; R⁵ represents hydrogen or an organic grouphaving a skeleton selected from those shown below

[0060] (wherein Q represents O or S; T represents CH₂, NH, S or O; lrepresents an integer of 0 to 5; and m and n independently representintegers of not less than 0, the total of m and n being not more than 5;each of said organic groups may have at least one substituent selectedfrom the group consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano,isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy);

[0061] R⁶ represents C₁-C₅ alkyl or allyl; and X⁻ represents apharmaceutically acceptable counter ion].

[0062] In Formula (II), as R¹, C₁-C₅ alkyl, C₄-C₇ cycloalkylalkyl, C₅-C₇cycloalkenylalkyl, C₇-C₁₃ aralkyl, C₄-C₇ alkenyl and allyl arepreferred, and methyl, ethyl, propyl, butyl, isobutyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenethyl,trans-2-butenyl, 2-methyl-2-butenyl and allyl are especially preferred.More preferred are methyl, ethyl, propyl, butyl, isobutyl,cyclopropylmethyl, benzyl, phenethyl and allyl.

[0063] As R², hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyland propyl are preferred, and hydrogen, hydroxy, acetoxy and methoxy areparticularly preferred.

[0064] As R³, hydrogen, hydroxy, C₁-C₅ alkanoyloxy and C₁-C₅ alkoxy arepreferred, and hydrogen, hydroxy, acetoxy and methoxy are particularlypreferred.

[0065] As R⁴, hydrogen, C₁-C₅ linear or branched alkyl and C₆-C₁₂ arylare preferred, and C₁-C₅ linear or branched alkyl, particularly, methyl,ethyl, propyl, isopropyl, butyl and isobutyl are especially preferred.

[0066] As A, C₁-C₆ alkylene, —CH═CH— and —C≡C— are preferred, and—CH═CH— and —C≡C— are particularly preferred.

[0067] As R⁵, hydrogen and organic groups having skeletons shown below

[0068] (wherein Q represents O or S; each of said organic groups mayhave at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy) are preferred.Especially preferred are phenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 3,4-difluorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-nitrophenhyl, 3-nitrophenhyl, 4-nitrophenhyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,3,4-dihydroxyphenyl, 3-furanyl, 2-furanyl, 3-thienyl, 2-thienyl,cyclopentyl and cyclohexyl, but examples of R⁵ are not restrictedthereto.

[0069] As R⁶, C₁-C₅ alkyl and allyl are preferred, and methyl isespecially preferred.

[0070] As the pharmaceutically preferred counterion X⁻, iodide ion,bromide ion, chloride ion, methanesulfonate and the like are preferred,but, needless to say, X⁻ is not restricted thereto.

[0071] Among the compounds represented by Formula (II), those wherein R¹is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl,benzyl or phenethyl; R² and R³ independently are hydrogen, hydroxy,acetoxy or methoxy; R⁴ is hydrogen or C₁-C₅ linear or branched alkyl; Ais —CH═CH— or —C≡C—; R⁵ is an organic group having a skeleton selectedfrom those shown below

[0072] (wherein Q represents O or S; each of said organic groups mayhave at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy);

[0073] R⁶ is methyl; and X⁻ is iodide ion, are preferred.

[0074] The compounds represented by Formula (II) may be produced by themethod described in WO98/23290.

[0075] The present invention also provides, particularly, a therapeuticagent for sepsis comprising, as an effective ingredient, an opioid κreceptor agonist compound which is morphinan-N-oxide derivativerepresented by the following Formula (III):

[0076] [wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₆-C₁₂ aryl, C₇-C₁₃aralkyl, C₄-C₇ alkenyl or allyl; R2 represents hydrogen, hydroxy, nitro,C₁-C₅ alkanoyloxy, C₁-C₅ alkoxy or C₁-C₅ alkyl; R³ represents hydrogen,hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; R⁴ represents hydrogen,C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl; A represents C₁-C₆alkylene, —CH═CH— or —C≡C—; R⁵ represents hydrogen or an organic grouphaving a skeleton selected from those shown below

[0077] (wherein T represents CH₂ or 0; 1 represents an integer of 0 to5; and m and n independently represent integers of not less than 0, thetotal of m and n being not more than 5; each of said organic groups mayhave at least one substituent selected from the group consisting ofC₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine,chlorine, bromine, iodine, nitro, cyano, isothiocyanato,trifluoromethyl, trifluoromethoxy and methylenedioxy)] or apharmaceutically acceptable acid addition salt thereof.

[0078] In Formula (III), as R¹, C₁-C₅ alkyl, C₄-C₇ cycloalkylalkyl,C₅-C₇ cycloalkenylalkyl, C₇-C₁₃ aralkyl, C₄-C₇ alkenyl and allyl arepreferred, and methyl, ethyl, propyl, butyl, isobutyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenethyl,trans-2-butenyl, 2-methyl-2-butenyl and allyl are especially preferred.More preferred are methyl, ethyl, propyl, butyl, isobutyl,cyclopropylmethyl, benzyl, phenethyl and allyl.

[0079] As R², hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyland propyl are preferred, and hydrogen, hydroxy, acetoxy and methoxy areparticularly preferred.

[0080] As R³, hydrogen, hydroxy, acetoxy and methoxy are preferred.

[0081] As R⁴, hydrogen, C₁-C₅ linear or branched alkyl and phenyl arepreferred, and C₁-C₅ linear or branched alkyl are especially preferred.Among these, methyl, ethyl, propyl, isopropyl butyl and isobutyl areparticularly preferred.

[0082] As A, C₁-C₆ alkylene, —CH═CH— and —C≡C— are preferred, and—CH═CH— and —C≡C— are particularly preferred.

[0083] As R⁵, hydrogen and organic groups having skeletons shown below

[0084] (each of said organic groups may have at least one substituentselected from the group consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano,isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy)are preferred. Especially preferred are phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 2-nitrophenhyl, 3-nitrophenhyl,4-nitrophenhyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3-furanyl,2-furanyl, cyclopentyl and cyclohexyl, but, needless to say, R⁵ is notrestricted to these examples.

[0085] Among the compounds represented by Formula (III), preferred arethose wherein R¹ is methyl, ethyl, propyl, butyl, isobutyl,cyclopropylmethyl, allyl, benzyl or phenethyl; R² and R³ independentlyare hydrogen, hydroxy, acetoxy or methoxy; R⁴ is hydrogen or C₁-C₅linear or branched alkyl; A is —CH═CH— or —C≡C—; R⁵ is an organic grouphaving a skeleton selected from those shown below

[0086] (each of said organic groups may have at least one substituentselected from the group consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano,isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy).

[0087] The present invention also provides, particularly, a therapeuticagent for sepsis comprising, as an effective ingredient, an opioid κreceptor agonist compound which is represented by the following Formula(IV):

[0088] [wherein the wavy lines (˜) between the cyclohexane ring and thetwo nitrogen atoms represent bonds which are cis or trans with respectto the cyclohexane ring; A represents valence bond, —(CH₂)_(q)—,—CH(CH₃)— or —X(CH₂)_(n)— (wherein q represents an integer of 1 to 4; nrepresents an integer of 1 to 4; and X represents O or S); Ar representsa carbocyclic aromatic ring, heterocyclic aromatic ring, bicarbocyclicaromatic ring, tricarbocyclic aromatic ring or diphenylmethyl, each ofsaid carbocyclic aromatic ring, heterocyclic aromatic ring,bicarbocyclic aromatic ring, tricarbocyclic aromatic ring anddiphenylmethyl may have one or more substituents selected from the groupconsisting of hydrogen, halogen, trifluoromethyl, nitro, C₁-C₃ alkoxy,hydroxy, azide, C₁-C₃ alkyl, methanesulfonyl, cyano, amino, C₁-C₃alkoxycarbonyl, C₁-C₃ alkanoyloxy and C₁-C₃ acylamino represented by—NHC(═O)R⁷ (wherein R⁷ represents hydrogen or C₁-C₂ alkyl); R representshydrogen, C₁-C₃ alkyl or allyl; R¹ and R² independently representhydrogen, C₁-C₃ alkyl or allyl, or R¹, R² and the nitrogen atom to whichthey bind cooperatively represent azetidinyl, pyrrolidinyl,3-hydroxypyrrolidinyl, 3-fluoropyrrolidinyl, morpholinyl, piperidinyl or3,4-dehydropiperidinyl; R³, R⁴, R⁵ and R⁶ independently representhydrogen, hydroxy, OR⁸ or OC(═O)R⁹, or R⁵ and R⁶ cooperatively represent-E-CH₂—CH₂-E-, =E, —CH₂—CH₂—CH₂-Z- or —CH₂—CH₂-Z-CH₂— (wherein Zrepresents oxygen (—O—), —NR¹⁰—, sulfur (—S—), —S(═O)— or —S(═O)₂—; Erepresents N—OH, N—OC(═O)CH₃, oxygen or sulfur; R⁸ represents C₁-C₃alkyl; and R⁹ represents hydrogen or C₁-C₃ alkyl]

[0089] or a pharmaceutically acceptable acid addition salt thereof.

[0090] Among the compounds represented by Formula (IV), the followingcompounds are preferred:

[0091](±)-N-[2-(N,N-dimethylamino)cyclohexyl]-N-methyl-2-(4-trifluoromethylphenyl)acetamide,

[0092](±)-N-[2-(N,N-dimethylamino)cyclohexyl]-N-propyl-2-(3-methoxyphenyl)acetamide,

[0093](±)-N-[2-(N,N-dimethylamino)cyclohexyl]-N-methyl-2-(4-azidophenyl)acetamide,

[0094](±)-N-[2-(N,N-dimethylamino)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide,

[0095](±)-N-[2-(N,N-dimethylamino)cyclohexyl]-N-methyl-2-(4-methoxyphenyl)acetamide,

[0096](±)-N-[2-(N,N-dimethylamino)cyclohexyl]-N-methyl-2-(2-naphthyl)acetamide,

[0097](±)-N-[2-(N-cyclopropyl-N-methylamino)cyclohexyl]-N-methyl-2-(4-azidophenyl)acetamide,

[0098](±)-N-[2-(3-acetoxy-1-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide,

[0099](±)-N-[2-(N-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide,

[0100](±)-N-[2-(3-hydroxypyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide,

[0101](±)-N-[2-(N-(3-hydroxy-1-azetidinyl))cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide,

[0102](±)-N-[2-(N,N-diethylamino)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide,

[0103](±)-N-[2-(N-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)propionamide,

[0104](±)-N-[2-(4-methyl-1-piperazinyl)cyclohexyl]-2-(3,4-dichlorophenyl)acetamide,

[0105](±)-N-[2-(N,N-dimethylamino)cyclohexyl]-2-(3,4-dichlorophenyl)acetamide,

[0106](±)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-7-yl]benzacetamide,

[0107](±)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzacetamide,

[0108](±)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-6-yl]benzacetamide,

[0109](±)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzacetamide,

[0110](±)-3-fluoro-N-ethyl-N-[7-(1-azetidinyl)-1,4-dioxaspiro[4.5]dec-8-yl]benzacetamide,

[0111](±)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.4]non-8-yl]benzacetamide,

[0112](±)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]undec-8-yl]benzacetamide,

[0113](±)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]undec-7-yl]benzacetamide,

[0114](±)-3,4-dichloro-N-methyl-N-[9-(1-pyrrolidinyl)-1,4-dioxaspiro[4.6]undec-8-yl]benzacetamide,

[0115](±)-3,4-dichloro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0116](±)-3,4-dichloro-N-[5-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0117](±)-3,4-dichloro-N-methyl-N-[4-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzacetamide,

[0118](±)-4-bromo-N-methyl-N-[2-(N,N-dimethylamino)-4-oxo-cyclohexyl]benzacetamide,

[0119](±)-N-[4-acetyloxy-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbenzacetamide,

[0120](±)-N-[4-acethyloxy-2-aminocyclohexyl]-3,4-difluoro-N-methylbenzacetamide,

[0121](±)-3,4-dichloro-N-[5-(hydroxyimino)-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0122](±)-3,4-dichloro-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide

[0123](±)-3,4-dichloro-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide(or(±-3,4-dichloro-N-methyl-N-[4-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzacetamidedimethylketal),

[0124](±)-3,4-dichloro-N-[5,5-diethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0125](±)-(1α,2β)-3,4-dichloro-N-[4,4-dimethoxy-2-(pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0126](±)-4-trifluoromethyl-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0127](±)-3-trifluoromethyl-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0128](±)-3-hydroxy-4-methyl-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0129](±)-4-methanesulfonyl-N-[4,4-dimethoxy-2-(1-piperidinyl)cyclohexyl]-N-methylbenzamide,

[0130](±)-4-acetyloxy-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0131](±)-N-[4,4-bis(methylthio)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbenzacetamide,

[0132](±)-N-[5,5-bis(ethylthio)-2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbenzacetamide,

[0133](±)-3,4-dichloro-N-[4-methylthio-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0134](±)-3,4-dichloro-N-[5-ethylthio-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0135](±)-3,4-dichloro-N-[6-methylthio-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0136](±)-3,4-dichloro-N-[4-mercapto-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0137][1R-(1α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-4-benzofuranacetamide,

[0138][1S-(1α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-4-benzofuranacetamide,

[0139][1R-(1α,2β,4α,5α)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-4-benzofuranacetamide,

[0140][1S-(1α,2β,4α,5α)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-4-benzofuranacetamide,

[0141][1R-(1α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzo[b]thiophen-4-acetamide,

[0142][1S-(1α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzo[b]thiophen-4-acetamide,

[0143][1R-(1α,2β,4α,5α)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzo[b]thiophen-4-acetamide,

[0144][1S-(1α,2β,4α,5α)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzo[b]thiophen-4-acetamide,

[0145][1R-(1α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-naphthaleneacetamide,

[0146][1S-(1α,2β,4α,5α)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-naphthaleneacetamide,

[0147][1R-(1α,2β,4α,5α)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-naphthaleneacetamide,

[0148][1S-(1α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-naphthaleneacetamide,

[0149][1R-(1α,2β,4β,5β)]-3,4-dichloro-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0150][1S-(1α,2β,4β,5β)]-3,4-dichloro-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0151][1R-(1α,2β,4α,5α)]-3,4-dichloro-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0152][1S-(1α,2β,4α,5α)]-3,4-dichloro-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzacetamide,

[0153][1R-(1α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide,

[0154][1S-(1α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide,

[0155][1R-(1α,2β,4α,5α)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide,

[0156][1S-(1α,2β,4α,5α)]-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide,

[0157](±)-(1α,2β,4β)-N-methyl-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-4-benzofuranacetamide,

[0158](±)-(1α,2β,4α)-N-methyl-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-4-benzofuranacetamide,

[0159](±)-(1α,2β,5β)—N-methyl-N-[5-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-4-benzofuranacetamide,

[0160](±)-(1α,2β,5α)-N-methyl-N-[5-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-4-benzofuranacetamide,

[0161](±)-(1α,2β,4α)-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide,

[0162](±)-(1α,2β,5β)-N-[5-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide,

[0163](±)-N-methyl-2-(1-naphthalenyloxy)-N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide,

[0164](±)-N-methyl-2-(2-naphthalenyloxy)-N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide,

[0165](±)-1,2-dihydro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-1-acenaphthylenecarboxamide(isomer I. mixture of (1α,2β) and (1β,2α)),

[0166](±)-1,2-dihydro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-1-acenaphthylenecarboxamide(isomer II. mixture of (1α,2β) and (1β,2α)),

[0167](±)-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-1,2-dihydro-N-methyl-1-acenaphthylenecarboxamide(isomer I. mixture of(1α,2β,4β,5β) and (1β,2α,4α,5α)),

[0168](±)-1,2-dihydro-N-[4-methoxy-2-(pyrrolidinyl)cyclohexyl]-N-methyl-1-acenaphthylenecarboxamide(isomer I. mixture of (1α,2β,4β) and (1β,2α,4α)),

[0169](±)-1,2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-acenaphthylenecarboxamide(isomer II. mixture of (1α,2β,4β) and (1β,2α,4α)),

[0170](±)-1,2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-acenaphthylenecarboxamide(isomers I and II. mixture of (1α,2β,4β) and (1α,2β,4α)),

[0171](±)-1,2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-acenaphthylenecarboxamide(isomers I and II. mixture of (1β,2α,4α) and (1α,2β,4β)),

[0172](±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-9H-fluorene-9-carboxamide,

[0173](±)-trans-1,3-dihydro-1-oxo-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-4-isobenzofuranacetamide,

[0174](±)-(1α,2β,4β,5β)-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-1,3-dihydro-N-methyl-1-oxo-4-isobenzofuranacetamide,

[0175](±)-(5α,7α,8β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5] dec-8-yl]benzacetamide,

[0176](±)-(5α,7β,8β)-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzacetamide,

[0177](±)-(5α,7α,8β)-4-methoxy-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzacetamide,

[0178](±)-(5α,7α,8β)—N-methyl-2-nitro-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzacetamide,

[0179](±)-(5α,7α,8β)—N-methyl-3-nitro-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzacetamide,

[0180](±)-(5α,7α,8β)-N-methyl-4-nitro-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzacetamide,

[0181](±)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-3-(trifluoromethyl)benzacetamide,

[0182](±)-(5α,6α,7β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-6-yl]benzacetamide,

[0183](±)-(5α,7α,8β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzacetamide,

[0184](±)-(5α,7β,8α)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-7-yl]benzacetamide,

[0185](±)-(5α,7α,8β)-3,4-dichloro-N,N-dimethyl-N-[7-(1-pyrrolidinyl)-1-azaspiro[4.5]dec-8-yl]benzacetamide,

[0186](±)-(5α,7α,8β)-4-bromo-N-methyl-N-[7-(1-pyrrolidinyl)-1-azaspiro[4.5]dec-8-yl]benzamide,

[0187](±)-(5α,7α,8β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzamide,

[0188](±)-(5α,7α,8β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzacetamide,

[0189](±)-(5α,7α,8β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzacetamide1-oxide,

[0190](±)-(5α,7α,8β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-thiaspiro[4.5]dec-8-yl]benzacetamide1,1-oxide,

[0191](±)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-azaspiro[4.5]dec-8-yl]-4-trifluoromethylbenzacetamide,

[0192](±)-(5α,7α,8β)—N-methyl-N-[8-(1-pyrrolidinyl)-1-azaspiro[4.5]dec-7-yl]-3-trifluoromethylbenzacetamide,

[0193][(5R)-(5α,7α,8β)]-N-methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-1H-indene-3-acetamide,

[0194][(5S)-(5α,7α,8β)]-N-methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-1H-indene-3-acetamide,

[0195][(5R)-(5α,7β,8α)]-N-methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-1H-indene-3-acetamide,

[0196][(5S)-(5α,7β,8α)]-N-methyl-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-1H-indene-3-acetamide,

[0197][(5R)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-1H-indole-3-acetamide,

[0198][(5S)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-1H-indole-3-acetamide,

[0199][(5R)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-1H-indole-3-acetamide,

[0200][(5S)-(5α,7α,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-1H-indole-3-acetamide,

[0201][(5R)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-2-benzofuranacetamide,

[0202][(5S)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-2-benzofuranacetamide,

[0203][(5R)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-2-benzo[b]furanacetamide,

[0204][(5S)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-2-benzo[b]futranacetamide,

[0205][(5R)-(5α,7β,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-3-benzo[b]furanacetamide,

[0206][(5S)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-3-benzo[b]furanacetamide,

[0207][(5R)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-3-benzo[b]furanacetamide,

[0208][(5S)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-3-benzo[b]furanacetamide,

[0209][(5R)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide,

[0210][(5S)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide,

[0211][(5R)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide,

[0212][(5S)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide,

[0213][(5R)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]thiophene-4-acetamide,

[0214][(5S)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]thiophene-4-acetamide,

[0215][(5R)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]thiophene-4-acetamide,

[0216][(5S)-(5α,7β,8α)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]thiophene-4-acetamide,

[0217](−)-(5α,7α,8β)—N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide,

[0218](±)-(5α,7α,8β)-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4-benzo[b]thiophene-4-acetamide,

[0219](±)-(5α,6α,7β)-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-2-oxaspiro[4.5]dec-6-yl]benzacetamide,

[0220](±)-(5α,6α,7β)-3,4-dichloro-N-methyl-N-[6-(1-pyrrolidinyl)-2-oxaspiro[4.5]dec-7-yl]benzacetamide,and

[0221](±)-(5α,7α,8β)-3,4-dichloro-N-methyl-N-[8-(1-pyrrolidinyl)-2-oxaspiro[4.5]dec-7-*yl]benzacetamide,

[0222] The compounds represented by Formula (IV) may be produced by themethods described in U.S. Pat. No. 4,145,435 (1979), U.S. Pat. No.4,360,531 (1982), U.S. Pat. No. 4,359,476 (1982), EP Patent No. 108602(1983), U.S. Pat. No. 4,855,316 (1989), European Patent No. 372466(1989), European Patent No. 393696 (1990), U.S. Pat. No. 4,906,655(1990), U.S. Pat. No. 4,438,130 (1984), U.S. Pat. No. 4,663,343 (1987)and U.S. Pat. No. 5,760,023 (1998).

[0223] The present invention also provides, particularly, a therapeuticagent for sepsis comprising, as an effective ingredient, an opioid κreceptor agonist compound which is represented by the following Formula(V):

(D)Phe-R1-R2-R3-Q  (V)

[0224] [wherein R1 represents (D)NapAla or (D)Phe; R2 represents (D)Nle,Trp or (D)Ile; R3 represents (D)Arg or (D)ChAla; Q is a C-terminalstructure of the peptide and represents —(C═O)OH or —(C═O)NXY (wherein Xrepresents hydrogen or C₁-C₆ alkyl; and Y represents hydrogen or C₁-C₆alkyl)]

[0225] or a pharmaceutically acceptable acid addition salt thereof.

[0226] Among the peptide compounds described above, preferred are(D)Phe-(D)NapAla-(D)Nle-(D)Arg-NH₂,(D)Phe-(D)NapAla-(D)Nle-(D)ChAla-NH₂, (D)Phe-(D)NapAla-Trp-(D)Arg-NH₂,(D)Phe-(D)NapAla-Trp-(D)ChAla-NH₂, (D)Phe-(D)NapAla-(D)Ile-(D)Arg-NH₂,(D)Phe-(D)NapAla-(D)Ile-(D)ChAla-NH₂, (D)Phe-(D)Phe-(D)Nle-(D)Arg-NH₂,(D)Phe-(D)Phe-(D)Nle-(D)CIiAla-NH₂, (D)Phe-(D)Phe-Trp-(D)Arg-NH₂,(D)Phe-(D)Phe-Trp-(D)ChAla-NH₂, (D)Phe-(D)Phe-(D)Ile-(D)Arg-NH₂ and(D)Phe-(D)Phe-(D)Ile-(D)ChAla-NH₂. Peptide compounds described inJapanese Laid-open PCT application No. 11-512075 (1999), in which theC-terminals are not amidized, and the peptide compounds which are amidesof which C-terminals are substituted with one or two substituents, aswell as pharmaceutically acceptable salts thereof, may also be employed.

[0227] Standard procedures for synthesizing peptides are well-known inthe art, and the above-described peptide compounds may be prepared bythe methods described in Japanese Laid-open PCT application No.11-512075 (1999) and WO99/32510.

[0228] Preferred examples of the pharmaceutically acceptable acidaddition salts of the compounds represented by Formulae (I), (III) and(IV) include inorganic acid salts such as hydrochloric acid salt,sulfuric acid salt, nitric acid salt, hydrobromic acid salt, hydroiodicacid salt and phosphoric acid salt; organic carboxylic acid salts suchas acetic acid salt, lactic acid salt, citric acid salt, oxalic acidsalt, glutaric acid salt, malic acid salt, tartaric acid salt, fumaricacid salt, mandelic acid salt, maleic acid salt, benzoic acid salt andphthalic acid salt; and organic sulfonic acid salts such asmethanesulfonic acid salt, ethanesulfonic acid salt, benzenesulfonicacid salt, p-toluenesulfonic acid salt and camphorsulfonic acid salt.Among these, hydrochloric acid salt, hydrobromic acid salt, phosphoricacid salt, tartaric acid salt and methanesulfonic acid salt arepreferred, but the pharmaceutically acceptable acid addition salts arenot restricted thereto.

[0229] The compounds represented by Formula (I) to (V) or thepharmaceutically acceptable acid addition salts thereof may beadministered orally or parenterally as they are or in the form ofpharmaceutical compositions after being admixed with knownpharmaceutically acceptable acids, carriers or vehicles, after beingpurified to the level suitable for medical use and after passing therequisite safety tests. Examples of administration forms includeinjection solutions; oral formulations such as tablets, capsules,granules, powders and syrups; and enteral formulations such assuppositories. The therapeutic agent according to the present inventionmay preferably contain the above-described effective ingredient at aconcentration of 1 to 90% by weight, more preferably 30 to 70% byweight. The administration dose may be appropriately selected dependingon the age, bodyweight, administration method and so on. For an adult,the administration dose may be 0.0001 mg to 1 g per day in case ofinjection solutions, and 0.005 mg to 10 g per day in case of oralformulations, and the drug may be administered once a day or dividedlyseveral times per day.

[0230] The compounds represented by Formula (I) to (V) or thepharmaceutically acceptable acid addition salts thereof may be used asan effective ingredient individually or in combination.

[0231] The compounds represented by Formula (I) to (V) or thepharmaceutically acceptable acid addition salts thereof may be usedtogether with drugs used for therapy or prevention of sepsis, such asantibiotics, antibacterial agents, anti-endotoxin antibodies,anti-cytokine drugs (including anti-cytokine antibodies, solublecytokine receptors, inhibitors of cytokine production and cytokineantisense RNAs), or with drugs used for diseases accompanying sepsis,such as steroids; protease inhibitors such as aprotinin, urinastatin,gabexate mesilate and nafamostat mesilate; pentoxifylline andPGG-glucan. They may also be used together with cardiovascular agonistsaiming at restoration of circulating blood volume (dopamine, dobutamine,isoproterenol, norepinephrine); diuretics such as furosemide andmannitol; heparins, antithrombin and activated protein C aiming atanti-coagulation; and G-CSF, γ-globulin and the like aiming at promotionof defense. They may also be combined with preventions and therapiesused for sepsis or diseases accompanying sepsis, such asendotoxin-adsorption therapy, blood-purification therapy based ondialysis and filtration, nutritional treatment, infusion therapy and thelike. The drugs and therapies which may be co-employed are notrestricted to those mentioned above.

[0232] The diseases to which the therapeutic agent for sepsis accordingto the present invention is applied include sepsis caused by infections,injury, invasions such as burn and various surgical invasions such asthotacolaparotomy and organ transplantations. Sepsis caused by diseasessuch as acute pancreatitis, peritonitis, cirrhosis, renal failure,diabetes and dystocia, and by therapies against injury or diseases, suchas indwelling catheter, transfusion device and dialysis are alsoincluded. Diseases accompanying sepsis, such as organ dysfunction,severe sepsis complicated with hypoperfusion or hypotension, lacticacidosis, hypouresis and septic shock complicated with consciousnessdisorder are also included. Further, disseminated intravascularcoagulation syndrome (DIC), adult respiratory distress syndrome (ARDS),multiple organ dysfunction (MODS) and the like are also included.Further, under special pathological conditions, sepsis accompanying notonly intractable blood diseases such as infectious endocarditis, acuteleukemia and anaplastic anemia, but also granulocytopenia in therapiesaccompanying suppression of bone marrow, such as cancer chemotherapiesand bone marrow transplantation, and acquired immune deficiencysyndrome, are included.

[0233] The present invention will now be described more concretely byway of examples.

Example 1 Evaluation of Therapeutic Action against Sepsis

[0234] ICR mice (bodyweight of 25g to 35 g when starting theexperiments) were raised in a plastic cage under SPF andthermo-hydrostat (22+1° C., 55±5%) conditions under 12-hour light-darkcycle. Foods and water were supplied ad libitum. Lipopolysaccharide(LPS)-induced lethal sepsis which is generally employed as anexperimental sepsis model was induced by intrapectoneally administeringLPS at a dose of 15 mg/kg. Two hours after administration of LPS whensymptoms of sepsis such as diarrhea, worsening of coat of fur andbradykinesia well appeared,(−)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloric acid salt 1

[0235] dissolved in physiological saline was subcutaneously administeredto the back of each mouse at a dose of 0.1 mg/kg, and the survival ofthe animals thereafter was tested. To the control group, physiologicalsaline was administered in place of Compound 1. The results are shown inFIG. 1. The survival rate at 24 hours after administration of LPS(induction of sepsis) was 30% in the control group and 80% in the groupto which Compound I was administered. The survival rates after 48 hoursof the control group and the Compound 1-administered group were 10% and40%, respectively. Thus, it was shown that Compound 1 has a therapeuticeffect against sepsis. Compound 1 may be produced in accordance with themethod described in Japanese Patent No. 2525552.

Example 2 Evaluation of Therapeutic Action against Sepsis

[0236] ICR mice (bodyweight of 25 g to 35 g when starting theexperiments) were raised in a plastic cage under SPF andthermo-hydrostat (22±1° C., 55±5%) conditions under 12-hour light-darkcycle. Foods and water were supplied ad libitum. Lipopolysaccharide(LPS)-induced lethal sepsis which is generally employed as anexperimental sepsis model was induced by intrapectoneally administeringLPS at a dose of 20 mg/kg. Two hours after administration of LPS whensymptoms of sepsis such as diarrhea, worsening of coat of fur andbradykinesia well appeared,(±)-N-[2-(N-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamidemethanesulfonic acid salt 2

[0237] dissolved in physiological saline was subcutaneously administeredto the back of each mouse at a dose of 15 mg/kg, and the survival of theanimals thereafter was tested. To the control group, physiologicalsaline was administered in place of Compound 2. The survival rate at 24hours after administration of LPS (induction of sepsis) was 33.3% in thecontrol group and 60% in the group to which Compound 2 was administered.Thus, it was shown that Compound 2 has a therapeutic effect againstsepsis. Compound 2 may be produced in accordance with the methoddescribed in U.S. Pat. No. 4,145,435 (1979).

Example 3 Evaluation of Therapeutic Action against Sepsis

[0238] ICR mice (bodyweight of 25 g to 35 g when starting theexperiments) were raised in a plastic cage under SPF andthermo-hydrostat (22±1° C., 55±5%) conditions under 12-hour light-darkcycle. Foods and water were supplied ad libitum. Lipopolysaccharide(LPS)-induced lethal sepsis which is generally employed as anexperimental sepsis model was induced by intrapectoneally administeringLPS at a dose of 20 mg/kg. Two hours after administration of LPS whensymptoms of sepsis such as diarrhea, worsening of coat of fur andbradykinesia well appeared, (D)Phe-(D)Phe-(D)Nle-(D)Arg-NH₂ dissolved inphysiological saline was subcutaneously administered to the back of eachmouse at a dose of 15 mg/kg, and the survival of the animals thereafterwas tested. To the control group, physiological saline was administeredin the same manner. The survival rate at 24 hours after administrationof LPS (induction of sepsis) was 33.3% in the control group and 66.7% inthe group to which (D)Phe-(D)Phe-(D)Nle-(D)Arg-NH₂ was administered.Thus, it was shown that (D)Phe-(D)Phe-(D)Nle-(D)Arg-NH₂ has atherapeutic effect against sepsis. The above-described peptide compoundmay be produced in accordance with the methods described in JapaneseLaid-open PCT Application No. 11-512075 (1999) or WO99/32510.

Example 4 Evaluation of Therapeutic Action against Sepsis

[0239] ICR mice (bodyweight of 25 g to 35 g when starting theexperiments) were raised in a plastic cage under SPF andthermo-hydrostat (22±1° C., 55±5%) conditions under 12-hour light-darkcycle. Foods and water were supplied ad libitum. Similar to otherexamples, experimental sepsis was induced by intraperitonealadministration of lipopolysaccharide (LPS) at a dose of 20 mg/kg.Thereafter,17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl-N′-3-trifluoromethylbenzylureido)morphinantartaric acid salt 3

[0240] dissolved in physiological saline was subcutaneously administeredto the back of each mouse at a dose of 3 mg/kg, and the survival of theanimals thereafter was tested. To the control group, physiologicalsaline was administered in the same manner. The survival rate at 31hours after administration of LPS (induction of sepsis) was 30.0% in thecontrol group and 70.0% in the group to which17-cyclopropylmethyl-3,140-dihydroxy-4,5α-epoxy-6β-(N-methyl-N′-3-trifluoromethylbenzylureido)morphinantartaric acid salt 3 was administered. Thus, it was shown that17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl-N′-3-trifluoromethylbenzylureido)morphinantartaric acid salt 3 has a therapeutic effect against sepsis. Compound 3may be produced in accordance with the method described in JapanesePatent No. 2525552.

1. A therapeutic agent for sepsis comprising an opioid κ receptoragonist compound as an effective ingredient.
 2. The therapeutic agentfor sepsis according to claim 1, wherein said opioid K receptor agonistcompound is a morphinan derivative or a pharmaceutically acceptable acidaddition salt thereof.
 3. The therapeutic agent for sepsis according toclaim 2, wherein said opioid K receptor agonist compound is a morphinanderivative represented by the following Formula (I):

[wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₆-C₁₂ aryl, C₇-C₁₃aralkyl, C₄-C₇ alkenyl, allyl, C₁-C₅ furan-2-ylalkyl or C₁-C₅thiophene-2-ylakyl; R² represents hydrogen, hydroxy, nitro, C₁-C₅alkanoyloxy, C₁-C₅ alkoxy, C₁-C₅ alkyl or —NR⁹R¹⁰ wherein R⁹ representshydrogen or C₁-C₅ alkyl and R represents hydrogen or C₁-C₅ alkyl or—C(═O)R¹¹ wherein R¹¹ represents hydrogen, phenyl or C₁-C₅ alkyl; R³represents hydrogen, hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; Arepresents —XC(═Y)—, —XC(═Y)Z-, —X— or —XSO₂— (wherein X, Y and Zindependently represent NR⁴, S or O wherein R⁴ represents hydrogen,C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl, R⁴s in the formula may bethe same or different); B represents valence bond, C₁-C₁₄ linear orbranched alkylene (with the proviso that said alkylene may have at leastone substituent selected from the group consisting of C₁-C₅ alkoxy,C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino,nitro, cyano, trifluoromethyl and phenoxy, and that 1 to 3 methylenegroups in said alkylene may be substituted with carbonyl group(s)),C₂-C₁₄ linear or branched acyclic unsaturated hydrocarbon containing 1to 3 double bonds and/or triple bonds (with the proviso that saidacyclic unsaturated hydrocarbon may have at least one substituentselected from the group consisting of C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy,hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano,trifluoromethyl and phenoxy, and that 1 to 3 methylene groups in saidacyclic unsaturated hydrocarbon may be substituted with carbonylgroup(s)), or C₁-C₁₄ linear or branched saturated or unsaturatedhydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or aminobonds (with the proviso that a hetero atom does not directly binds to A,and that 1 to 3 methylene groups in said acyclic unsaturated hydrocarbonmay be substituted with carbonyl group(s)); R represents hydrogen or anorganic group having a skeleton selected from those shown below

(wherein Q represents NH, O or S; T represents CH₂, NH, S or O; lrepresents an integer of 0 to 5; and m and n independently representintegers of not less than 0, the total of m and n being not more than 5;each of said organic groups may have at least one substituent selectedfrom the group consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro,cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy andmethylenedioxy); R⁶ represents hydrogen; R⁷ represents hydrogen,hydroxy, C₁-C₅ alkoxy or C₁-C₅ alkanoyloxy; or R⁶ and R⁷ cooperativelyrepresent —O—, —CH₂— or —S—; and R⁸ represents hydrogen, C₁-C₅ alkyl orC₁-C₅ alkanoyl] or a pharmaceutically acceptable acid addition saltthereof.
 4. The therapeutic agent for sepsis according to claim 3,wherein in said Formula (I), R¹ is methyl, ethyl, propyl, butyl,isobutyl, cyclopropylmethyl, allyl, benzyl or phenethyl; R² and R³independently are hydrogen, hydroxy, acetoxy or methoxy; A is —XC(═Y)—(wherein X represents NR⁴, S or O; Y represents O wherein R⁴ representshydrogen or C₁-C₅ alkyl), —NR⁴C(═Y)Z- (wherein Y represents O or S; Zrepresents NR⁴ or O wherein R⁴ represents hydrogen or C₁-C₅ alkyl),—NR⁴— (wherein R⁴ represents C₁-C₅ alkyl) or —NR⁴SO₂— (wherein R⁴represents hydrogen or C₁-C₅ alkyl); B is C₁-C₃ linear alkylene,—CH═CH—, —C≡C—, —CH₂—O—, —CH₂—S— or —CH₂—NH—; R⁵ is hydrogen or anorganic group having a skeleton selected from those shown below

(wherein Q represents O or S; each of said organic groups may have atleast one substituent selected from the group consisting of C₁-C₅ alkyl,C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine,iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl,trifluoromethoxy and methylenedioxy); R⁶ and R⁷ cooperatively represent—O—; and R⁸ is hydrogen.
 5. The therapeutic agent for sepsis accordingto claim 4, wherein in said Formula (I), A is —NR₄C(═O)— or —NR₄C(═O)O—(wherein R⁴ represents C₁-C₅ alkyl).
 6. The therapeutic agent for sepsisaccording to claim 4, wherein in said Formula (I), A is—NR₄C(═O)NR⁴—(wherein R⁴ represents C₁-C₅ alkyl).
 7. The therapeuticagent for sepsis according to claim 2, wherein said opioid K receptoragonist compound is a morphinan quaternary ammonium salt derivativerepresented by the following Formula (II):

[wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, C₅-C₇ cycloalkenylalkyl, C₇-C₁₃ aralkyl, C₄-C₇alkenyl or allyl; R² represents hydrogen, hydroxy, nitro, C₁-C₅alkanoyloxy, C₁-C₅ alkoxy or C₁-C₅ alkyl; R³ represents hydrogen,hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; R⁴ represents hydrogen,C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl; A represents C₁-C₆alkylene, —CH═CH— or —C≡C—; R⁵ represents hydrogen or an organic grouphaving a skeleton selected from those shown below

(wherein Q represents O or S; T represents CH₂, NH, S or O; l representsan integer of 0 to 5; and m and n independently represent integers ofnot less than 0, the total of m and n being not more than 5; each ofsaid organic groups may have at least one substituent selected from thegroup consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy,hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano,isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy);R⁶ represents C₁-C₅ alkyl or allyl; and X represents a pharmaceuticallyacceptable counter ion].
 8. The therapeutic agent for sepsis accordingto claim 7, wherein in said Formula (II), R¹ is methyl, ethyl, propyl,butyl, isobutyl, cyclopropylmethyl, allyl, benzyl or phenethyl; R² andR³ independently are hydrogen, hydroxy, acetoxy or methoxy; R⁴ ishydrogen or C₁-C₅ linear or branched alkyl; A is —CH═CH— or —C≡C—; R⁵ isan organic group having a skeleton selected from those shown below

(wherein Q represents O or S; each of said organic groups may have atleast one substituent selected from the group consisting of C₁-C₅ alkyl,C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine,iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxyand methylenedioxy); R⁶ is methyl; and X⁻ is iodide ion.
 9. Thetherapeutic agent for sepsis according to claim 2, wherein said opioid Kreceptor agonist compound is a oxide-N-oxide derivative represented bythe following Formula (III):

[wherein

represents a double bond or single bond; R¹ represents C₁-C₅ alkyl,C₄-C₇ cycloalkylalkyl, c₅-C₇ cycloalkenylalkyl, C₆-C₁₂ aryl, C₇-C₁₃aralkyl, C₄-C₇ alkenyl or allyl; R² represents hydrogen, hydroxy, nitro,C₁-C₅ alkanoyloxy, C₁-C₅ alkoxy or C₁-C₅ alkyl; R³ represents hydrogen,hydroxy, C₁-C₅ alkanoyloxy or C₁-C₅ alkoxy; R⁴ represents hydrogen,C₁-C₅ linear or branched alkyl or C₆-C₁₂ aryl; A represents C₁-C₆alkylene, —CH═CH— or —C_C—; R⁵ represents hydrogen or an organic grouphaving a skeleton selected from those shown below

(wherein T represents CH₂ or O; l represents an integer of 0 to 5; and mand n independently represent integers of not less than 0, the total ofm and n being not more than 5; each of said organic groups may have atleast one substituent selected from the group consisting of C₁-C₅ alkyl,C₁-C₅ alkoxy, C₁-C₅ alkanoyloxy, hydroxy, fluorine, chlorine, bromine,iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxyand methylenedioxy)] or a pharmaceutically acceptable acid addition saltthereof.
 10. The therapeutic agent for sepsis according to claim 9,wherein in said Formula (III), R¹ is methyl, ethyl, propyl, butyl,isobutyl, cyclopropylmethyl, allyl, benzyl or phenethyl; R² and R³independently are hydrogen, hydroxy, acetoxy or methoxy; R⁴ is hydrogenor C₁-C₅ linear or branched alkyl; A is —CH═CH— or —C≡C—; R⁵ is anorganic group having a skeleton selected from those shown below

(each of said organic groups may have at least one substituent selectedfrom the group consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano,isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy).11. The therapeutic agent for sepsis according to claim 1, wherein saidopioid K receptor agonist compound is a compound represented by thefollowing Formula (IV):

[wherein the wavy lines (˜) between the cyclohexane ring and the twonitrogen atoms represent bonds which are cis or trans with respect tothe cyclohexane ring; A represents valence bond, —(CH₂)_(q)—, —CH(CH₃)—or —X(CH₂)_(n)— (wherein q represents an integer of 1 to 4; n representsan integer of 1 to 4; and X represents O or S); Ar represents acarbocyclic aromatic ring, heterocyclic aromatic ring, bicarbocyclicaromatic ring, tricarbocyclic aromatic ring or diphenylmethyl, each ofsaid carbocyclic aromatic ring, heterocyclic aromatic ring,bicarbocyclic aromatic ring, tricarbocyclic aromatic ring anddiphenylmethyl may have one or more substituents selected from the groupconsisting of hydrogen, halogen, trifluoromethyl, nitro, C₁-C₃ alkoxy,hydroxy, azide, C₁-C₃ alkyl, methanesulfonyl, cyano, amino, C₁-C₃alkoxycarbonyl, C₁-C₃ alkanoyloxy and C₁-C₃ acylamino represented by—NHC(═O)R⁷ (wherein R⁷ represents hydrogen or C₁-C₂ alkyl); R representshydrogen, C₁-C₃ alkyl or allyl; R¹ and R² independently representhydrogen, C₁-C₃ alkyl or allyl, or R¹, R² and the nitrogen atom to whichthey bind cooperatively represent azetidinyl, pyrrolidinyl,3-hydroxypyrrolidinyl, 3-fluoropyrrolidinyl, morpholinyl, piperidinyl or3,4-dehydropiperidinyl; R³, R⁴, R⁵ and R⁶ independently representhydrogen, hydroxy, OR⁸ or OC(═O)R⁹, or R⁵ and R⁶ cooperatively represent-E-CH₂—CH₂-E-, =E, —CH₂—CH₂—CH₂-Z- or —CH₂—CH₂-Z-CH₂— (wherein Zrepresents oxygen (—O—), —NR¹⁰—, sulfur (—S—), —S(═O)— or —S(═O)₂—; Erepresents N—OH, N—OC(═O)CH₃, oxygen or sulfur; R⁸ represents C₁-C₃alkyl; and R⁹ represents hydrogen or C₁-C₃ alkyl] or a pharmaceuticallyacceptable acid addition salt thereof.
 12. The therapeutic agent forsepsis according to claim 1, wherein said opioid K receptor agonistcompound is a compound represented by the following Formula (V):(D)Phe-R1-R2-R3-Q  (V) [wherein R1 represents (D)NapAla or (D)Phe; R2represents (D)Nle, Trp or (D)Ile; R3 represents (D)Arg or (D)ChAla; Q isa C-terminal structure of the peptide and represents —(C═O)OH or—(C═O)NXY (wherein X represents hydrogen or C₁-C₆ alkyl; and Yrepresents hydrogen or C₁-C₆ alkyl)] or a pharmaceutically acceptableacid addition salt thereof.
 13. Use of said opioid κ receptor agonistcompound according any one of claims 1 to 11 for the production of atherapeutic agent for sepsis.
 14. A therapeutic method for sepsiscomprising administering said opioid κ receptor agonist compoundaccording any one of claims 1 to 11 to a patient suffering from sepsis.